Medullary thyroid cancer (MTC) is a neuroendocrine tumor derived from the calcitonin-producing thyroid C-cells and accounts for 3-5% of cases of thyroid cancer. Besides surgery, there are limited curative and palliative treatments available to patients with MTC, emphasizing the need for development of other forms of therapy. We have shown that over-expression of raf-1 markedly suppresses cellular growth and induces differentiation of human MTC cells in vitro. We have also shown that these raf-1 effects can be mediated through leukemia inhibitory factor (LIF), a soluble cytokine currently in clinical use for central nervous system disorders. However, the role of raf-1 and LIF in modulating MTC growth and differentiation in vivo has not been explored. In this proposal we will further characterize the downstream events required for raf-1-mediated MTC growth suppression and differentiation. Secondly, we will determine if raf-1 activation can inhibit in vivo MTC tumor growth in a mouse model of metastatic MTC. These studies should determine if modulation of the raf-1 signaling pathway, either by direct activation or through LIF signaling, could play a potential role in the management of patients with metastatic MTC. Because LIF has been already utilized in human subjects for treatment of central nervous system disorders, if our animal data validates our in vitro observations, clinical trials with LIF in patients with metastatic MTC could happen in the near future.